Zinc involvement in opioid addiction and analgesia--should zinc supplementation be recommended for opioid-treated persons?

Diana Ciubotariu,Cătălina Elena Lupușoru,Cristina Mihaela Ghiciuc

doi:10.1186/s13011-015-0025-2

Abstract

IntroductionZinc chelators were shown to facilitate some opioid-withdrawal signs in animals. Zinc deficiency, which affects more than 15 % the world’s population, is also common among opioid consumers and opioid-treated animals exhibit misbalances of zinc distribution.AimThe present study focuses on how zinc ions interfere with opioid dependence/addiction and analgesia, trying to preliminary discuss if zinc supplementation in opioid-users should be recommended in order to reduce the risk of addiction.MethodsAll relevant literature was searched up to April 2015. The search was performed using the term “zinc” plus combinations of following terms: “opioid receptors”, “opioid” or representatives of this class, “addiction”, “dependence”, “analgesia”, and “pain”. Human, animal, in vitro studies and reviews were including.ResultsBoth human and animal studies revealed decreased serum zinc under opioid-administration conditions, attributed mainly to increased urinary elimination (humans) or redistribution (animals). Moreover, animal studies revealed decreased brain zinc levels in morphine-treated animals, with increased zinc hepatic levels, but also an enhancement of endogenous opioid system activity and a possible reduction of morphine withdrawal by zinc. In vitro studies revealed reduction of opioid ligands binding to receptors by zinc. However, the very few in vivo animal studies on opioid analgesia revealed controversial results, as zinc demonstrated clear analgesic effect, but zinc associated to opioids doesn’t result in a potentiation of the analgesic effect.ConclusionZinc dietary supplementation in patients treated with opioids for cancer-related chronic pain should be considered, due to the high incidence of zinc deficiency, also well-documented in opioid consumers. The low toxicity of orally-administered zinc also pleads for this idea. The main contra-argument to zinc administration in opioid-treated persons is related to the way zinc influences opioid-induced analgesia.

Highlights

Zinc chelators were shown to facilitate some opioid-withdrawal signs in animals
We have included articles containing information about: 1. zinc homeostasis in opioid consumers and opioidtreated animals compared to opioid-free individuals; 2. 1. the influence determined by zinc ions or zinc deficiency on the intensity of opioid-binding to specific and non-specific receptors; 2. 2. the influence determined by zinc ions or zinc deficiency on the activity level of endogenous opioidergic system; 3. the influence determined by zinc administration and zinc deficiency in animal models of opioid dependence and on the intensity of human opioid-addiction; 4. the influence of zinc ions or zinc deficiency on human and animal pain perception under opioid-free and opioid administration conditions
The initial search-results provided the below-mentioned number of articles: 1. zinc + opioid: 133 articles; 2. zinc + opioid + receptor: 57 articles; 3. zinc + pain: 531 articles; 4. zinc + analgesia: 28 articles; 5. zinc + algesia: 34 articles; 6. zinc + addiction + opioid: 6 articles; 7. zinc + dependence + opioid: 7 articles

Summary

Introduction

Zinc chelators were shown to facilitate some opioid-withdrawal signs in animals. Zinc deficiency, which affects more than 15 % the world’s population, is common among opioid consumers and opioid-treated animals exhibit misbalances of zinc distribution. The second most abundant trace element in the human body (after iron) [1], plays mainly catalytic and structural roles [2]; as a co-factor of Cu-Zn superoxide dismutase, it is important for the anti-oxidant defence [3]. The brain is one of the organs with high Zn2+ concentration, as it contains approximately 1.5 % of the estimated 2 to 3 g of zinc in the human body. Brain-zinc is non-uniformly distributed: the olfactory bulb has the highest level, followed by the frontal and parietal cortices, the striatum and the hippocampus; the lowest levels. Distribution vary with the age: in rats, at birth, cerebellum has the highest zinc level; within time, the hippocampus and the cortex levels increase [13, 14]. Neuronal Zn2+ is either bound to various proteins (over 90 %, with structural or catalytic roles and roles in transcription factors and related proteins) or free (mainly localized within the vesicles of zincdependent glutamatergic neurons) [15]

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